Abstract
T lymphocytes (T cells) undergo metabolic reprogramming after activation to provide energy and biosynthetic materials for growth, proliferation and differentiation. Distinct T cell subsets, however, adopt metabolic programs specific to support their needs. As CD4 T cells coordinate adaptive immune responses while CD8 T cells become cytotoxic effectors, we compared activation-induced proliferation and metabolic reprogramming of these subsets. Resting CD4 and CD8 T cells were metabolically similar and used a predominantly oxidative metabolism. Following activation CD8 T cells proliferated more rapidly. Stimulation led both CD4 and CD8 T cells to sharply increase glucose metabolism and adopt aerobic glycolysis as a primary metabolic program. Activated CD4 T cells, however, remained more oxidative and had greater maximal respiratory capacity than activated CD8 T cells. CD4 T cells were also associated with greater levels of ROS and increased mitochondrial content, irrespective of the activation context. CD8 cells were better able, however, to oxidize glutamine as an alternative fuel source. The more glycolytic metabolism of activated CD8 T cells correlated with increased capacity for growth and proliferation, along with reduced sensitivity of cell growth to metabolic inhibition. These specific metabolic programs may promote greater growth and proliferation of CD8 T cells and enhance survival in diverse nutrient conditions.
Highlights
Prior to activation, T lymphocytes (T cells) are quiescent and use only low rates of metabolism to fuel migration and homeostatic proliferation
After 72 h, CD3 and CD28 stimulation CD8 T cells showed a greater dilution of CellTrace Violet in comparison to CD4 cells, indicating increased proliferation in the CD8 cells (Fig. 1B)
Propidium iodide assessment of cell cycle status indicated that similar percentage of activated CD4 and CD8 T cells were in the S and G2 phases of the cell cycle after 72 h activation (Fig. 1C)
Summary
T lymphocytes (T cells) are quiescent and use only low rates of metabolism to fuel migration and homeostatic proliferation. Once activated by antigen presenting cells, CD4 and CD8 T cells proliferate rapidly and undergo environmentally directed differentiation into diverse effector cell populations. These effector cells optimize the immune response for specific pathogenic challenges. Activation and the transition from naıve to effector lymphocyte greatly alters cellular metabolic demands, as cells require both ATP and biosynthetic components to fuel growth, cell division, migration, and subset differentiation [1]. CD8 cytotoxic T cells have been shown to adopt a highly glycolytic metabolism [5,6], but transition to fatty acid oxidation as memory cells [7]
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